Abstract Head and Neck Squamous Cell Carcinoma (HNSCC) occurs frequently, ranking as the sixth leading cause of cancer deaths worldwide. Metastasis and recurrence result in a 5-year survival after surgery of around 20%. Therefore, there is a dire need for therapeutic strategies that can prevent metastasis and recurrence. The cancer stem cell (CSC) population is of growing interest, as accumulating evidence suggests these cells play a pivotal role in the ability of a tumor to seed a metastatic site and cause long term recurrence. Traditional chemotherapy drugs that target rapidly dividing cells often leave this subpopulation behind. In epithelial tissue, stem cell populations express high levels of the transcription factor p63. This p53 related protein is crucial for maintaining the undifferentiated stem cell phenotype of these epithelial cells. I propose that the CSC population of HNSCC is equally reliant on the expression of p63 to maintain the undifferentiated state. Understanding the exact isoform of p63 that is regulating this phenotype in CSCs and the pathways it controls, will provide new therapeutic targets for patients with this deadly disease. Preliminary data, along with previous work by our lab has implicated chromatin regulating proteins as key targets of p63 in epithelial tissue. Therefore, this proposal aims to elucidate the various chromatin regulators modulated by p63, that are essential for the survival of HNSCC CSCs, leading to new, lifesaving drug targets. Additionally, the work outlined in this proposal will help me develop new bench skills essential to furthering our understanding of cancer biology, including ChIP-Seq, RNA-Seq, flow cytometry, and the development of mouse models and CRISPR library screens. I will also benefit from additional career development including training in grant writing, written and oral scientific presentation, and student mentoring.